Monoallelic Methylation of the APC Promoter Is Altered in Normal Gastric Mucosa Associated with Neoplastic Lesions

Abstract

Adenomatous polyposis coli (APC) promoter hypermethylation has been reported frequently in normal gastric mucosa, but it remained to be clarified whether this occurs in every individual. In this study, methylation of the APC promoter was analyzed in histologically normal-appearing gastric mucosa samples by methylation-sensitive single-strand conformation analysis and by a methylation-sensitive dot blot assay. Epithelial cell samples were collected by microdissection from tissue sections. Equal amounts of methylated and unmethylated APC alleles were found in all gastric mucosa samples from patients without any gastric lesions (20 samples). Allele-specific methylation analysis showed that the methylation of the APC promoter was monoallelic; however, which allele was methylated depended on the cell type. Increased or decreased methylation was found in 10 of 36 (28%) normal gastric mucosa samples adjacent to a gastric or esophageal adenocarcinoma. No allelic loss was found at the APC locus. Modification of the methylation status was also found in 3 of 21 (14%) normal-appearing gastric mucosa samples adjacent to intestinal metaplasia. In contrast, all normal mucosa samples in cases with chronic gastritis but without metaplasia or dysplasia showed a monoallelic methylation pattern. Our results indicate the following: (a) In normal gastric mucosa, the APC promoter shows monoallelic methylation, which is not due to imprinting but most likely due to allelic exclusion; (b) the excluded allele differs between foveolar and glandular epithelial cells; (c) the APC methylation pattern is frequently altered in normal-appearing gastric mucosa of gastric or esophageal adenocarcinoma patients; and (d) such alterations also occur in normal gastric mucosa adjacent to intestinal metaplasia.

Methylation of the Tumor Suppressor Gene RUNX3 in Human Gastric Carcinoma

“…Monoallelic methylation of the APC promoter was reported to be altered in normal gastric mucosa associated with the neoplastic lesions. 29 Similar observations were made on the tumor suppressor gene GPx3, with respect to the promoter hypermethylation in Barrett's esophagus. 30 These findings suggest that monoallelic methylation is common and the methylation of one allele may indicate the start of an early stages of tumorigenesis.…”

Analysis of APC and IGFBP7 promoter gene methylation in Swedish and Vietnamese colorectal cancer patients

“…The reported methylation status of the promoter of APC varies greatly among studies of CRC in different populations (16)(17)(18)(19)(20). Moreover, hypermethylation of the APC promoter has been shown to be relatively common in other gastrointestinal neoplasms, including those of the stomach, liver, pancreas and oesophagus (17,29).…”

Methylation status of the APC and RASSF1A promoter in cell-free circulating DNA and its prognostic role in patients with colorectal cancer

“…The rate of APC promoter methylation in CRC and normal colorectal mucosa has been reported to range from 11 to 62% in different populations, and has been suggested to moderate the Wnt signaling pathway (25)(26)(27)(28)(29). Furthermore, hypermethylation of the APC promoter has been demonstrated to be relatively common in other gastrointestinal neoplasms, including those of the stomach, liver, pancreas and oesophagus (30).…”